Complications of natural rubella infection or immunization with attenuated rubella vaccine in 25% of adult women include transient and chronic arthritis. Understanding the events leading to complications due to live RV vaccine would potentially lead to improvement in future RV vaccines. To understand the mechanisms of RV -associated pathology, we are analyzing the function of both the essential elements of virus RNA and their interaction with host and viral components during viral replication. We have identified two host-encoded proteins La and calreticulin,that are known autoantigens and are essential for RV replication. The involvement of autoantigens in RV pathogenesis is of clinical interest, because antibodies to autoantigens is common occurance in autoimmune diseases. We have found that sera from patients with Sjorgens syndrome and Systemic Lupus Erythrematous have antibodies against RV-autoantigen complexes. The antibody response to RV-autoantigen complexes in autoimmune patients suggests that similar mechanism may occur in RV-associated arthropathy. The project deals directly with the safety issues of live- viral vaccines in general and of RV vaccine in particular. Research conducted with RV will serve as a guideline for understanding the vaccine related adverse reactions such as RV vaccine-associated acute or chronic arthritis. It also provides insight in the design of future viral vaccines that must be free of adverse effects. Further, we have developed in-house know-how of modern techniques used in development of recombinant viral vaccines currently being developed by the companies. Thus, enabling the agency to provide guidance to the manufacturers in such issues. Outcome of RV research has also an added impact on the development of assays and methodologies which are useful in evaluating the purity of biologics during manufacturing process and lot release testing. Knowledge gained from the research done with RV can provide impetus in the development of regulatory policy to evaluate manufacturing process for live-viral vaccines as well as recombinant vaccines that isefficient and less cumbersome.